Alzheimer's disease (AD) is characterized by a progressive decline of cognitive processes such as learning and memory. The hippocampus is involved in learning and memory and is affected in AD patients. Learning and memory also occurs with normal aging. It is believed that learning and memory processes may be mediated by synaptic plasticity. The major goal of these studies is to investigate the duration of long-term potentiation, a form of synaptic plasticity in the aged impaired animals and the effect of aging on gene expression during learning of a hippocampal-dependent spatial learning and long-term potentiation in vivo freely moving animals. In Specific Aim I experiments will characterize animals that are aged impaired or aged unimpaired in spatial learning. Animals will be used for permanent electrode implantation in the medial or lateral perforant path-CA3 synapse to investigate the duration of long-term potentiation at these synapses. In Specific Aim 2 experiments will investigat e the temporal and spatial mRNA expression of a number of candidate genes and cytochrome oxidase activity during learning. In aged impaired and aged unimpaired animals, experiments will compare the mRNA expression of hzf-3, tPA, agrin, and LAG by using in situ hybridization, and the activity of cytochrome oxidase by using histochemical techniques. In Specific Aim 3 experiments will investigate mRNA expression of hzf-3, tPA , agrin and LAG and the activity of cytochrome oxidase activity in long-term potentiation in the medial and lateral perforant path-CA3 synapse. The research findings from the proposed studies have important implications to aging research. A long-standing notion in learning and memory is that modifications of synaptic connections within the nervous system may underlie learning and memory processes. If permanent changes in synaptic modifications occur during learning, these changes must also be reflected at the genetic level. Thus if both a decrease in synaptic plastic ity and a decrease in gene expression is observed in aged impaired in spatial learning animals, then this a relationship between aged related impairment in learning and gene expression may shed light into the mechanisms associated with cognitive impairment associated with aging. Further, a decrease in.'cytochrome oxidase activity in learning and synaptic plasticity will suggest that this enzyme is important in cognitive processes.